Introduction
The intestine not only serves as a barrier against external harmful
agents and pathogen infection, but also interacts with commensal
microbiome and food antigens. Therefore, the intestinal immune system
reacts to both inner and external environments to maintain homeostasis.
When this balance is disrupted, chronic inflammatory disorders can occur
in the intestine, leading to inflammatory bowel disease (IBD) (Maloy &
Powrie, 2011). There are two main forms of IBD: Crohn’s disease, which
includes inflammatory disorder throughout the gastrointestinal tract,
and ulcerative colitis, which is restricted in the colon (Kaser,
Zeissig, & Blumberg, 2010). Causes of IBD is complicated. It involves
multiple factors such as genetic factors, failure of the host immune
system, and disruption of gut microbiota (Hill & Artis, 2010; Podolsky,
1991).
Macrophages are innate immune cells well distributed in almost all
tissues and are highly heterogenous to achieve niche-specific functions.
Gut macrophages not only can maintain immune homeostasis by driving
clearance of infection, but also can control oral tolerance and tissue
repair (Mazzini, Massimiliano, Penna, & Rescigno, 2014; Murray & Wynn,
2011). Gut macrophages initiate inflammation in response to stimuli such
as pathogen or cell damage. After an inflammatory response takes place,
complete resolution must take place to maintain homeostasis. Gut
macrophages are key players initiating inflammation to stimuli such as
infection, but also in resolution of inflammation afterwards.
Dysfunction of macrophages may result in failure of resolution, leading
to chronic inflammation (Na, Stakenborg, Seok, & Matteoli, 2019).
Alternatively activated macrophages can produce anti-inflammatory
cytokines IL-10 and growth factors such as TGF-β, prostaglandin
E2 (PGE2), bone morphogenetic protein 2
(BMP2), and WNT ligands (Lin et al., 2010; Wynn & Vannella, 2016).
IL-10 production is known to promote immunosuppressive
CD4+ regulatory T cells (Treg).
Gut macrophages contain self-maintaining resident macrophages derived
from embryonic birth and bone marrow derived macrophages matured from
circulating monocytes (Viola & Boeckxstaens, 2021). Freshly supplied
bone marrow derived Ly6Chi monocytes undergo
differentiation into CX3CR1+macrophages in the lamina propria (Bain et al., 2014). They rapidly
upregulate major histocompatibility complex type II (MHCII) and
downregulate Ly6C. During colitis,
CX3CR1int expressing monocytes are
recruited to the gut. They show a pro-inflammatory phenotype. Mature
CX3CR1hi macrophages are rather
anti-inflammatory. They can maintain homeostasis (Diehl et al., 2013;
Geissmann, Jung, & Littman, 2003; Viola & Boeckxstaens, 2021).
IBD patients show altered differentiation of macrophages compared to
healthy individuals. Since functional macrophage defect can lead to
chronic inflammatory disorders, macrophages can be considered a
potential target for IBD treatment. Previous studies have shown that
macrophages have distinct phenotypes through metabolic regulation.
Inflammatory macrophages show enhanced glycolysis while
anti-inflammatory macrophages show enhanced oxidative phosphorylation
(Russell, Huang, & VanderVen, 2019; Wculek et al., 2023). Distinct
pathways of arginine metabolism determine macrophage characters.
Inflammatory macrophages express nitric oxide synthase which leads to
production of nitric oxide and citrulline, while anti-inflammatory
macrophages express arginase which leads to production of urea and
ornithine (Rath, Muller, Kropf, Closs, & Munder, 2014). Also,
inflammatory macrophages can be induced by accumulation of citrate or
succinate due to impairment of the TCA cycle (Harber et al., 2020;
Palmieri et al., 2020). Thus, utilizing metabolic modulation to induce
macrophage polarization can be a therapeutic approach to treat IBD.
In this study, we introduce LMT503, an IBD therapeutic candidate, which
act as a substrate for NADH quinone oxidoreductase 1 (NQO1), a
multi-functional protein that can increase cellular
NAD+, drive oxidation-reduction reaction, and
stabilize proteins such as p53 (Nebert, Roe, Vandale, Bingham, &
Oakley, 2002; Ross & Siegel, 2021). Increased NAD+ by
NQO1 can activate sirtuins and drive metabolic modulation of macrophages
to have an anti-inflammatory character (S. Y. Park et al., 2017). The
objective of this study was to determine whether LMT503 could induce
polarization of macrophages to an immune-suppressive type to alleviate
colitis in a DSS-induced murine model.